(W-016) Revumenib physiologically based pharmacokinetic model for evaluation of age effect and CYP3A4-mediated drug-drug interaction in relapsed/refractory acute leukemias

Alenka Chapron, PhD – PBPK Consultant, Certara; Zoe Barter, PhD – PBPK Consultant, Certara; Hannah Jones, PhD – SVP, Head of PBPK Consultancy, Certara; Steven Smith, PhD – Consultant, Syndax Pharmaceuticals, Inc.; Gary Maier, PhD – President and Founder, MaierMetrics and Associates LLC; Peter Ordentlich, PhD – Chief Scientific Officer, Syndax Pharmaceuticals, Inc.; Joshua Stewart, BS – Syndax Pharmaceuticals, Inc., Syndax Pharmaceuticals, Inc.; Soujanya Sunkaraneni, MS Pharm – Senior Director, Clinical Pharmacology, Syndax Pharmaceuticals, Inc.

Objectives: Clinical pharmacology of revumenib, a selective, oral, small-molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction under investigation in patients with acute leukemias,¹ has been determined in clinical and modeling studies. Here, we report the development and application of a PBPK model to assess the effects of age and co-administration with CYP3A4 inhibitors (CYP3A4i) or CYP3A4 inducers on the PK of revumenib.

Methods: The PBPK model was developed and verified using clinical data from adult and pediatric patients (0.75 to 81 years [yrs]) in AUGMENT-101 [NCT04065399]. Model verification involved recovery of revumenib exposure in the presence of weak, moderate, and strong CYP3A4i that were concomitantly administered. The model was in general agreement, with most revumenib exposures within 2-fold of observed data. The model was applied with multiple dose simulations to support dose adjustments to target pediatric exposures equivalent to those in adults after revumenib 276 mg twice daily (BID) without a CYP3A4i. Doses were predicted in 8 pediatric age groups: 1 to < 2 months (mo), 2 to < 4 mo, 4 to < 6 mo, 6 mo to < 1 yr, 1 to < 2 yrs, 2 to < 4 yrs, 4 to < 8 yrs, 8 to 16 yrs. Multiple-dose adult and pediatric simulations were repeated in the presence of moderate/strong CYP3A4 inducers, and weak/moderate/strong CYP3A4i.

Results: Simulations suggested similar exposure in pediatric patients aged 6 mo to 16 yrs to those in adults when dosed on a mg/m² basis (AUC_^tau range, 10629–13178 h.ng/mL). However, a 1.6–2.3-fold increase in revumenib exposure was predicted in infants aged 1 to < 6 mo (AUC_^tau range, 14731–21805 h.ng/mL). The proposed starting dose in pediatric patients 1 to < 2 mo is 70 mg/m², and for 2 to < 6 mo old is 100 mg/m². Beyond BSA-based adjustment, no dose adjustment is necessary in pediatric patients ≥ 6 mo. Simulations predicted comparable drug–drug interaction liability in pediatric vs adult patients when co-administered with CYP3A4 perpetrators. Overall, 1.2–4.1-fold increases in AUC and 1.1–3.3-fold increases in C_max were predicted in the presence of weak/moderate/strong CYP3A4i in adult patients; 3.2–5.2-fold reductions AUC and 2.5–4-fold reductions in C_max were predicted in the presence of moderate/strong CYP3A4 inducers. The model and clinical data suggested dose reduction is needed for a strong CYP3A4i, and no dose adjustment is needed for moderate or weak CYP3A4i.

Conclusions: Based on PBPK modeling, revumenib exposure changes may require dose adjustment for pediatric patients aged 1 to < 6 months. No dose adjustment appears necessary in pediatric patients ≥ 6 months old. In the presence of a strong CYP3A4i, a dose reduction may be needed. No dose adjustment appears necessary with a moderate/weak CYP3A4i.

Citations: [1] Issa GC, et al. Nature. 2023;615:920–24.